rs150384171
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PM4_SupportingBS2
The NM_016579.4(CD320):c.262_264delGAG(p.Glu88del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,606,154 control chromosomes in the GnomAD database, including 102 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_016579.4 conservative_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00803 AC: 1216AN: 151518Hom.: 7 Cov.: 33
GnomAD3 exomes AF: 0.00936 AC: 2299AN: 245504Hom.: 12 AF XY: 0.00905 AC XY: 1207AN XY: 133364
GnomAD4 exome AF: 0.0110 AC: 15935AN: 1454522Hom.: 95 AF XY: 0.0107 AC XY: 7730AN XY: 723916
GnomAD4 genome AF: 0.00802 AC: 1216AN: 151632Hom.: 7 Cov.: 33 AF XY: 0.00791 AC XY: 586AN XY: 74058
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:3Other:1
PM4 -
This variant is associated with the following publications: (PMID: 20524213, 29040465, 29663633, 30041674, 22819238, 31180159, 31462756) -
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- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
CD320: PM4:Supporting, BS1, BS2 -
Methylmalonic acidemia due to transcobalamin receptor defect Pathogenic:2Uncertain:1Benign:1
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This variant, c.262_264del, results in the deletion of 1 amino acid(s) of the CD320 protein (p.Glu88del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs150384171, gnomAD 1.4%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with methylmalonic aciduria (PMID: 20524213, 22819238, 29663633, 34978764; internal data). ClinVar contains an entry for this variant (Variation ID: 203643). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CD320 function (PMID: 20524213, 27411955). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
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CD320-related disorder Pathogenic:1
The CD320 c.262_264delGAG variant is predicted to result in an in-frame deletion (p.Glu88del). This variant has been reported in the homozygous or compound heterozygous state in patients with methylmalonic acidemia and homocysteinemia due to transcobalamin receptor deficiency (e.g., Quadros et al. 2010. PubMed ID: 20524213; Karth et al. 2012. PubMed ID: 22819238; Hannah-Shmouni et al. 2018. PubMed ID: 29663633; Pappas et al. 2022. PubMed ID: 34978764). Fibroblast cells from patients apparently homozygous for the CD320 c.262_264del (p.Glu88del) variant showed reduced uptake of holo-transcobalamin (holo-TC) as well as elevated levels of homocysteine and methylmalonic acid in culture medium (Quadros et al. 2010. PubMed ID: 20524213; Pangilinan et al. 2022. PubMed ID: 35107211). The c.262_264del variant has been reported in a large population database at an allele frequency of up to ~1.4%, which would be high for an autosomal recessive disorder with a severe phenotype. It should be noted, however, that most reported patients with transcobalamin receptor deficiency have been clinically asymptomatic. These data suggest that this may possibly be a benign biochemical phenotype, although the long-term outcome in these individuals is not currently well understood (Hannah-Shmouni et al. 2018. PubMed ID: 29663633). In summary, we classify the c.262_264del (p.Glu88del) variant as likely pathogenic for recessive transcobalamin receptor deficiency. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at